Preparation of an Atorvastatin Intermediate

ABSTRACT

Atorvastatin lactone is prepared by hydrogenating tert-butyl isopropylidene nitrile to tert-butyl isopropylidene amine and condensing the amine with the diketone of atorvastatin to form acetonide ester. The diol protecting acetonide ester is deprotected to form a diol ester by dissolving the acetonide ester in methanol and treating with an acid. The diol ester is saponified to form a sodium salt. Methanol is removed from the reaction mixture by distillation. The sodium salt is reacidified to the free diol acid and atorvastatin lactone is formed from the diol acid. The atorvastatin lactone is directly dried without further purification.

INTRODUCTION

The invention relates to a process for preparing atorvastatin lactone.Atorvastatin lactone is a trans-6-[2-(substitutedpyrrole-1-yl)alkyl]pyran-2-one which is known by the chemical name(2R-trans)-5-(4-fluorophenyl)-2-(1-methyethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

Atorvastatin lactone is the penultimate intermediate in the preparationof another trans-6-[2-(substituted pyrrole-1-yl)alkyl]pyran-2-one,atorvastatin calcium known by the chemical name[R—R*,R*)]-2-(4-fluorophenyl-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt.

Atorvastatin as well as some of its metabolites is pharmacologicallyactive in humans and is useful as a hypolipidemic andhypocholesterolemic agent. In particular, atorvastatin is useful as aselective and competitive inhibitor of the enzyme3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, therate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme Ato mevalonate, a precursor of sterols such as cholesterol. Theconversion of HMG-CoA to mevalonate is an early and rate-limiting stepin cholesterol biosynthesis.

U.S. Pat. No. 4,681,893, which is herein incorporated by reference,discloses certain trans -6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

U.S. Pat. No. 5,273,995, which is herein incorporated by reference,discloses the enantiomer having the R form of the ring-opened acid oftrans -5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, i.e.,[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.

The above described atorvastatin compounds have been prepared by asuperior convergent route disclosed in the following U.S. Pat. Nos.5,003,080; 5,097,045; 5,103,024; 5,124,482 and 5,149,837 which areherein incorporated by reference and Baumann K. L., Butler D. E.,Deering C. F., et al, Tetrahedron Letters 1992;33:2283-2284.

One of the critical intermediates outlined in U.S. Pat. No. 5,097,045has also been produced using novel chemistry, as described in U.S. Pat.No. 5,155,251, which is herein incorporated by reference and Brower P.L., Butler D. E., Deering C. F., et al, Tetrahedron Letters1992;33:2279-2282.

U.S. Pat. Nos. 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792;5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691;5,5109,488; WO97/03960; WO98/09543 and WO99/32434 which are hereinincorporated by reference, disclose various processes and keyintermediates for preparing atorvastatin.

The process for preparing atorvastatin lactone is particularly sensitiveand vulnerable to the formation of process impurities which may causeproduct rejection and decreased yields.

The object of the present invention is to provide an improved processfor preparing atorvastatin lactone with increased yield and reducedcycle time.

STATEMENTS OF INVENTION

According to the present invention there is provided a process forpreparing atorvastatin lactone comprising the steps of:-

-   -   hydrogenating tert-butyl isopropylidene nitrile to tert-butyl        isopropylidene amine;    -   condensing tert-butyl isopropylidene amine thus formed with the        diketone of atorvastatin to form acetonide ester;    -   deprotecting the diol protecting acetonide ester to form a diol        ester- the acetonide ester being dissolved in methanol and        treated with an acid;    -   saponifying the diol ester to form a sodium salt;    -   removing methanol from the diol acid sodium salt mixture so that        the reaction mixture contains less than 3% w/v of methanol;    -   reacidifying the sodium salt to the free diol acid; and    -   forming atorvastatin lactone from the diol acid.

In a preferred embodiment the process includes the step of directlydrying the atorvastatin lactone without further purification.

Preferably the methanol is removed by distillation. Vacuum distillationis preferred. However, atmospheric distillation may alternatively beemployed.

DETAILED DESCRIPTION

The invention will be more clearly understood from the followingdescription given 5 by way of example only.

The process for preparing atorvastatin lactone, illustrated in scheme 1,comprises the steps of

-   -   hydrogenating tert-butyl isopropylidene nitrile to tert-butyl        isopropylidene amine using sponge nickel and isopropanol;    -   acid catalysed Paal-Knorr condensing of tert-butyl        isopropylidene amine thus formed with the diketone of        atorvastatin to form acetonide ester;    -   acid-catalysed deprotecting of the diol protecting acetonide        ester by dissolving the acetonide ester in methanol and treating        with an acid to form a diol ester;    -   saponifying the diol ester to form a sodium salt;    -   removing process impurities from the reaction mixture using        methyl tert butyl ether;    -   removing methanol from the reaction mixture by distillation at        approximately 70° C. under vacuum or approximately 99° C. at        atmospheric pressure leaving less than 3% w/v of methanol in the        reaction mixture;    -   reacidifying the sodium salt to the free diol acid; and    -   forming atorvastatin lactone from the diol acid.

The methyl ester of atorvastatin is a major impurity in crudeatorvastatin with typical levels at 1 to 1.5%.

We have surprisingly found that by reducing the level of residualmethanol present from approximately 10 to 15% to less than 3% w/v,especially levels as high as 2.6% w/v the level of the methyl esterimpurity in atorvastatin lactone is reduced to insignificant levels(≦0.1%).

In the present invention residual methanol is effectively removed fromthe reaction mixture using vacuum distillation or distillation at hightemperatures before acid is introduced in the reacidification of thesodium salt to the diol acid.

Distillation to remove methanol has been shown to result in asignificant decrease in the level of the atorvastatin methyl esterimpurity in isolated crude atorvastatin lactone.

Typically, before drying the pure product, recrystallisation of crudeatorvastatin lactone from toluene is carried out to remove processimpurities such as diol acid, methyl ester and other minor impurities.

However, we have found that the removal of methanol essentially removesthe methyl ester impurity from crude lactone and has the potential toincrease the product yield in the recrystallisation step as methyl esterimpurities are no longer present.

More significantly we have found that removal of the finalrecrystallisation step is now possible. Eliminating this additionalprocessing step results in an overall increase in yield of approximately3 to 5% with a significant reduction in the overall atorvastatin lactonepreparation time and equipment utilisation.

EXAMPLE 1: (Comparative)

50 g tert-butyl isopropylidene (TBIN), prepared as described inTetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28%ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are addedto a pressure vessel. The mixture is reduced with 50 psi of hydrogen,then filtered and concentrated in vacuo. The resulting oil is dissolvedin 250 ml warm toluene, water washed and again concentrated in vacuo togive an amino ester. The amino ester, 85 g4-fluoro-β-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenyl-benzenebutanamide(diketone of atorvastatin), 12.5 g pivalic acid, 137.5 mltetrahydrofuran (THF) and 137.5 ml hexanes are charged to an argoninerted pressure vessel which is sealed and heated to 75° C. for 96hours. After cooling the solution is diluted with 400 ml methyltert-butyl ether (MTBE) and washed firstly with dilute aqueous sodiumhydroxide followed by dilute aqueous hydrochloric acid. The mixture isthen concentrated in vacuo to give an acetonide ester.

The acetonide ester is dissolved in 275 ml warm methanol and aqueoushydrochloric acid (5 g of 37% hydrochloric acid in 75 ml of water) isadded. The mixture is stirred at 30° C. to produce a diol ester. 100 mlmethyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H₂O and25 g of 50% aqueous sodium hydroxide) are then added and the mixturestirred at 30° C. to produce a sodium salt. 600 ml water is added andthe mixture washed twice with 437.5 ml methyl tert-butyl ether.

Residual methyl tert-butyl ether and some methanol is removed from theaqueous layer by atmospheric distillation to a temperature of 87-90° C.The mixture is stirred at 75-85° C. for 18 hours, then cooled, acidifiedand extracted into 875 ml toluene. The mixture is heated at reflux for 4hours and water is removed azeotropically. After cooling, the mixture isfiltered and washed with toluene. The crude lactone is thenrecrystallised from toluene and lactone is isolated as an white solid.

-   Yield: 36 g; 59.8% from tert-butyl isopropylidene.-   Impurity level: crude Methyl ester 1.3%.    -   pure Methyl ester 0.6%.

EXAMPLE 2

50 g tert-butyl isopropylidene (TBIN), prepared as described inTetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28%ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are addedto a pressure vessel. The mixture is reduced with 50 psi of hydrogen,then filtered and concentrated in vacuo. The resulting oil is dissolvedin 250 ml warm toluene, water washed and again concentrated in vacuo togive an amino ester. The amino ester, 85 g4-fluoro-β-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenyl-benzenebutanamide(diketone of atorvastatin prepared by a method disclosed in U.S. Pat.No. 5,155,251 which is herein incorporated by reference and Bauman K. L,Butler D. E., Deering C. F., et al Tetrahedron Letters1992;33:2283-2284), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF)and 137.5 ml hexanes are charged to an argon inerted pressure vesselwhich is sealed and heated to 75° C. for 96 hours. After cooling thesolution is diluted with 400 ml methyl tert-butyl ether (MTBE) andwashed firstly with dilute aqueous sodium hydroxide followed by diluteaqueous hydrochloric acid. The mixture is then concentrated in vacuo togive an acetonide ester.

The acetonide ester is dissolved in 275 ml warm methanol and aqueoushydrochloric acid (5 g of 37% hydrochloric acid in 75 ml of water) isadded. The mixture is stirred at 30° C. to produce a diol ester. 100 mlmethyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H₂O and25 g of 50% aqueous sodium hydroxide) are then added and the mixturestirred at 30° C. to produce a sodium salt. 600 ml water is added andthe mixture washed twice with 437.5 ml methyl tert-butyl ether.

In this case, the mixture is distilled under atmospheric pressure to abatch temperature of 70-75° C. A vacuum of approximately −0.25 bar isthen applied and distillation is continued until the methanol content ofthe mixture is reduced to less than 2.6% w/v. The batch is stirred at75-85° C. for 18 hours, then cooled, acidified and extracted into 875 mltoluene. The mixture is heated at reflux for 4 hours and water removedazeotropically. After cooling the mixture is filtered, washed withtoluene and dried directly. Lactone is isolated as awhite solid.

-   Yield: 37.9 g; 63% from tert-butyl isopropylidene.-   Impurity level: Methyl ester 0.16%.

EXAMPLE 3

50 g tert-butyl isopropylidene (TBIN), prepared as described inTetrahedron Letters, 1992, 2279, 13.25 g wet sponge nickel catalyst, 28%ammonia solution (137.5 ml) and 375 ml isopropyl alcohol (IPA) are addedto a pressure vessel. The mixture is reduced with 50 psi of hydrogen,then filtered and concentrated in vacuo. The resulting oil is dissolvedin 250 ml warm toluene, water washed and again concentrated in vacuo togive an amino ester. The amino ester, 85 g4-fluoro-β-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenyl-benzenebutanamide(diketone of atorvastatin prepared by a method disclosed in U.S. Pat.No. 5,155,251 which is herein incorporated by reference and Bauman K. L,Butler D. E., Deering C. F., et al Tetrahedron Letters1992;33:2283-2284), 12.5 g pivalic acid, 137.5 ml tetrahydrofuran (THF)and 137.5 ml hexanes are charged to an argon inerted pressure vesselwhich is sealed and heated to 75° C. for 96 hours. After cooling thesolution is diluted with 400 ml methyl tert-butyl ether (MTBE) andwashed firstly with dilute aqueous sodium hydroxide followed by diluteaqueous hydrochloric acid. The mixture is then concentrated in vacuo togive an acetonide ester.

The acetonide ester is dissolved in 275 ml warm methanol and aqueoushydrochloric acid (5 g of 37% hydrochloric acid in 75 ml of water) isadded. The mixture is stirred at 30° C. to produce a diol ester. 100 mlmethyl tert-butyl ether and aqueous sodium hydroxide (150 ml of H₂O and25 g of 50% aqueous sodium hydroxide) are then added and the mixturestirred at 30° C. to produce a sodium salt. 600 ml water is added andthe mixture washed twice with 437.5 ml methyl tert-butyl ether.

In this case, the mixture is distilled under atmospheric pressure to abatch temperature of 99° C. Distillation is continued until the methanolcontent of the mixture is reduced to 0.4 w/v. The batch is stirred at75-85° C. for 18 hours, then cooled, acidified and extracted into 875 mltoluene. The mixture is heated at reflux for 4 hours and water isremoved azeotropically. After cooling, the mixture is filtered, washedwith toluene and dried directly. Lactone is isolated as a white solid.

-   Yield: 37.9 g; 63% from tert-butyl isopropylidene.-   Impurity level: Methyl ester 0.1%.

The invention is not limited to the embodiments hereinbefore describedwhich may be varied in detail.

1. A process for preparing atorvastatin lactone comprising the stepsof:- hydrogenating tert-butyl isopropylidene nitrile to tert-butylisopropylidene amine; condensing tert-butyl isopropylidene amine thusformed with the diketone of atorvastatin to form acetonide ester;deprotecting the diol protecting acetonide ester to form a diol ester bydissolving the acetonide ester in methanol and treating with an acid;saponifying the diol ester to form a sodium salt; removing methanol fromthe diol acid sodium salt reaction mixture so that the reaction mixtureincludes less than 3% w/v of methanol; reacidifying the sodium salt tothe free diol acid; and forming atorvastatin lactone from the diol acid.2. A process as claimed in claim 1 including the step of directly dryingthe atorvastatin lactone without further purification.
 3. A process asclaimed in claim 1 or 2 wherein methanol is removed from the diol acidsodium salt reaction mixture by distillation.
 4. A process as claimed inclaim 3 wherein methanol is removed from the diol acid sodium saltreaction mixture by vacuum distillation.
 5. A process as claimed inclaim 3 wherein the methanol is removed from the diol acid sodium saltreaction mixture by atmospheric distillation.